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Telomeres: a diagnosis at the end of the chromosomes
B B A de Vries, R Winter, A Schinzel, C van Ravenswaaij-Arts

J Med Genet 2003;40:385–398

In recent years, subtelomeric rearrangements have been identified as a major cause of mental retardation and/or malformation syndromes. So far, over 2500 subjects with mental retardation have been tested and reported of whom ∼ 5% appeared to have a subtelomeric rearrangement. In this review, the clinical aspects of each known (submicroscopic) subtelomeric deletion will be presented and the various methods available for detecting subtelomeric abnormalities will be discussed. Not only will the patients and their families benefit from a good collection and report of the various telomeric abnormalities and their clinical phenotype, but it will also give more insight into the aetiology of mental retardation and malformation syndromes.

See end of article for authors’ affiliations

Correspondence to: Dr B B A de Vries, Department of Human Genetics 417, University Hospital Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands;


ental retardation is a common handicap (2-3% of the general population) with an unknown cause in more than 50% of mentally retarded patients.1–4 Important causes are chromosome abnormalities which are detectable in 4-28% of cases, depending on the patient selection and techniques used.4 5 Deletions and/or translocations larger than 2-3 megabases (Mb) are mostly microscopically visible. 4p− (WolfHirschhorn), 5p− (cri du chat), 9p−, 13q−, and 18p− syndromes are examples of microscopically visible deletions that mostly include the subtelomeric region and cause mental retardation associated with a specific phenotype. For detecting submicroscopic subtelomeric abnormalities, Wilkie et al6 developed in 1993 a technique using hypervariable DNA polymorphisms. Two years later, Flint et al,7 using this method, identified previously undetectable abnormalities in 5% of 99 mentally retarded patients. This and other subsequent studies has led to the awareness that subtelomeric deletions below the level of the light microscope (<2-3 Mb) are a significant cause of malformation and mental retardation syndromes. In 1999, Knight et al8 reported a high rate of subtelomeric aberrations among children with moderate to severe mental retardation (IQ=50), whereas a lower yield was found in children with mild retardation (IQ 50-70) (7.4% versus 0.5%), thus again emphasising the importance of subtelomeric abnormalities in the former group of patients. Since then, several series of examinations of mentally retarded subjects, different in ascertainment, number of patients, and method used, have been reported (table 1). So far, over 2500 subjects have been tested and reported of whom ∼5% appeared


to have a subtelomeric rearrangement. Compared to another well known condition causing mental retardation, namely the fragile X syndrome, subtelomeric deletions seem to be a more frequent cause of MR. The fragile X syndrome can be diagnosed in ∼1-2% of the mentally retarded.4 9 10 The relative high frequency of subtelomeric deletions should be interpreted with caution for various reasons. Firstly, the cases chosen for performing the telomere screen are probably selected for the so called chromosomal phenotype.11 Secondly, a reporting bias may influence the frequency as studies showing a low yield are less likely to be published. However, even if the frequency is somewhat lower than 5% it still will be a considerable step forward in diagnosing a significant number of mentally retarded subjects and counselling the families involved. The yield of new cases identified may even significantly increase by preselection based on family history and physical features. One important selective feature is the level of mental retardation; more subtelomere defects are found among the moderately to severely mentally retarded compared to the mildly retarded.8 12 However, subtelomeric abnormalities have also been described among mildly mentally retarded subjects. Based on the common features observed in a series of subtelomeric cases, a checklist was developed to facilitate preselection of cases for subtelomere testing,11 13 including (1) family history of mental retardation, (2) prenatal onset growth retardation, (3) postnatal growth abnormalities (either poor or overgrowth), (4) >2 facial dysmorphic features, (5) one or more non-facial dysmorphic features and/or congenital abnormality. Rio et al14 found congenital anomalies, behavioural problems, and postnatal growth retardation to be the most common features in their series, whereas Riegel et al15 reported the presence of more than one affected member in the family as the most important selection criterion in addition to the mental retardation combined with dysmorphic features, with or without major malformations and growth retardation.

Mental retardation is the key feature in patients with subtelomeric defects. Some of the submicroscopic subtelomere deletions result in a specific phenotype which may direct the clinician towards the diagnosis. In these patients, FISH analysis of a single and specific subtelomere will be sufficient to confirm the diagnosis. However, the majority of cases with subtelomeric defects lack a characteristic phenotype, so far. For these cases a general subtelomere screen is required to achieve a diagnosis. For this group effective clinical preselection is essential because of the technical complexities and cost of screening for telomere deletions (see discussion).

which.40% of patients). and visual problems have been reported. Rossi et al12 reported another boy who was profoundly mentally retarded with pachygyria. Variable cardiac malformations. facial anomalies (upward slanting eyebrows. Another case with severe mental handicap. and orofacial clefting (10. The Ebstein heart anomaly.1%) 124 (4. and full round facies with periorbital fullness. Although a putative neuroblastoma tumour suppressor gene has been mapped to the 1p36. Slavotinek et al17 reviewed 39 patients with pure 1p36 monosomy. ear asymmetry.8%) 22 (4. a female fetus (17 weeks) with microretrognathia and a large midline cleft in addition to facial dysmorphism was found to have the same 1q monosomy and 13q trisomy as her brother. growth abnormalities (growth retardation. and characteristic facies. Both had a der(2)(t(2.13)(q44. a pointed chin.7%) 1 (2. Facially. microcephaly. and adducted thumbs was reported in the series of Rio et al.7%) 5 (4%) 1 (1. seizures. microcephaly. severe microcephaly.1-1p36. broad nasal base with fleshy nares.p11. the majority with a microscopically visible deletion. and toe syndactyly caused by a der(1)t(1q. and facial dysmorphism with a large anterior fontanelle.jmedgenet. depressed nasal bridge. and midface hypoplasia. Giraudeau et al21 found three 1p− patients among 567 mentally retarded subjects and Rio et al14 found three patients among 150 severely mentally retarded . smooth philtrum. prominent forehead. et al Table 1 Studies of subtelomeres in patients with idiopathic mental retardation Technique Persons tested 99 17 209 466 43 27 154 200 254 30 200 150 120 70 14 50 111 250 184 33 2570 Persons with telomeric defect 3 (6%) 4 (23. ages 2-14 years) developed neuroblastoma. smooth philtrum. One case had a de novo 1q44-qter deletion and the other der(1)t(1. hypospadias. 1q De Vries et al22 reported two unrelated boys with a submicroscopic terminal 1q44 deletion and growth and mental retardation. in general.4%) 5 (35. is very rare in chromosome aberrations.3 region. cardiomyopathy.386 De Vries. The mother’s chromosomes were normal and the father was not available for testing. cardiac abnormalities. 1p Shapira et al16 reported on clinical and molecular aspects of 1p36 deletion in 14 patients in 1997.3 deletion. pre.6%) 0 (0%) 16 (10.1). scoliosis. a thin upper lip. gastrooesophageal reflux. has been observed in at least three cases with 1p36. A profoundly mentally retarded boy with severe microcephaly.14 2p Riegel et al15 reported a 2 year old severely mentally retarded boy with severe microcephaly.7%) 2 (4%) 10 (9%) 9 (4%) 1 (0.3)mat was reported by Riegel et al. Schinzel.18)(q44. and a deletion of 1qter and a duplication of 1pter probably resulting from a large parental pericentric inversion. and confirmed the association with hypotonia. ptosis and ophthalmoplegia.3%) 2 (7.8%) Flint et al7 Viot et al159 Vorsanova et al60 Knight et al8 Lamb et al161 Slavotinek et al125 Ballif et al34 Rossi et al12 Riegel et al15 Borgione et al148 Joyce et al162 Rio et al14 Rosenberg et al80 Sismani et al73 Joly et al33 Clarkson et al31 Anderlid et al32 Baker et al23 Karnebeek et al163 Helias-Rodzewicz et al30 Hypervariable DNA polymorphism Multiprobe FISH Multiprobe FISH Multiprobe FISH Multiprobe FISH Multiprobe FISH FISH probes Multiprobe FISH Multiprobe FISH Multiprobe FISH + microsatellite Multiprobe FISH Microsatellite markers Microsatellite markers Multiprobe FISH + MAPH CGH + multiprobe FISH Multiprobe FISH Multiprobe FISH Multiprobe FISH Multiprobe FISH Multiprobe FISH Total In the following sections the submicroscopic subtelomeric deletions and their clinical presentation are described for each chromosome end.13). Fig 1 shows clinical photographs of various patients with subtelomere deletions. short distal phalanges.6%) 13 (6. mental retardation (usually severe). making it one of the more common cryptic subtelomeric deletions.3.2) detected www. In some cases.0%) 8 (3.2. callosum abnormalities. Winter. postaxial polydactyly of the left hand. and cryptorchidism. The authors suggested the location of gene(s) involved in normal midline development in the subtelomeric region of 1q. and seizures. they had short noses with a long.q34) caused by a balanced maternal t(1. and thin upper lip). and facial dysmorphism (long face. bilateral cleft lip and palate.and postnatal growth retardation. Using five highly polymorphic minisatellite probes for 1p36. and generalised amyotrophy and a der(1)t(1.7)(p25. A female fetus (sib) was terminated with microcephaly and bilateral cleft lip and palate. cleft palate. seizures. facial dysmorphism (not further specified). in the series of Wu et al20 none of the patients (n=30. the straight and low set eyebrows are striking and can be helpful in the diagnosis. obesity).5%) 13 (5%) 2 (6. In the same family. small palpebral fissures). corpus 2q Phelan et al24 25 reported four cases with apparent Albright hereditary osteodystrophy (AHO) and del(2)(37.15 Baker et al23 reported a 15 year old male with borderline IQ. Subsequently. ventricular dilatation. short stature but normal head circumference. almond shaped eyes with upward slanting palpebral fissures and thick eyebrows. sensorineural hearing loss. They also showed that the breakpoints were highly variable within 1p36 and that 21 out of 27 de novo deletions were maternally derived.5%) 3 (9.q36.14 18 19 Disturbed behaviour has been reported varying from temper outbursts to self-injurious behaviour. brachydactyly.4%) 4 (2. deep set eyes.12p).

Since then several other patients with an AHO-like phenotype and a submicroscopic 2q37.27 Ghaffari et al29 reported a 6 month old boy with craniofacial dysmorphism somewhat suggestive of Noonan syndrome. notably t(2.jmedgenet.30 Mildly mentally retarded patients with 2qter deletions and an inconsistent clinical phenotype have been reported31–33 and www. however. a few café au lait spots. Behaviour is generally friendly.3 microdeletion have been reported. and epilepsy.27 28 This AHO-like phenotype consists of mental retardation.q36) was detected in a severely cognitively retarded 3 year old boy with facial dysmorphism (prominent forehead.8)(q37. arched eyebrows. hyperkinesia.7)(q73. and one had a microdeletion at 2q37. some caused by a familial submicroscopic translocation. four had cytogenetically visible de novo deletions of chromosome 2q37.q24. brachymesophalangism. pectus carinatum. A der(2)t( .3. aggression. small mouth with short philtrum and thin upper lip). or psychiatric problems can be present. inguinal hernia.17q?). downward slanting palpebral fissures. self-mutilation. short stature. tetralogy of Fallot. round face. Wilson et al26 reported five other patients with brachymesophalangism and mental retardation.3) and t(2.3. long eyelashes. and a partial monosomy 2qter and trisomy 17qter detected by comparative genomic hybridisation (CGH).17) (q37. by high resolution chromosome analysis. and talipes equinovarus.Telomeres 387 Figure 1 Clinical photographs of various patients with subtelomere deletions.

which suggests that a deletion distal to 3p25. upward slanting palpebral fissures.10) (q35.37 Characteristic features of the 3p− syndrome include low birth weight. mild facial dysmorphism (mild epicanthic folds.20)(q35. Anderlid et al. Rossi et al12 described a cryptic 5p deletion resulting from a t(4p. Three out five patients died before the age of 2 years.52 The most typical feature of this syndrome. heart defects. Winter. mental retardation. heart defects (VSD). 3p deletion can either be of paternal or maternal origin. and bilateral vesicoureteric reflux. slender hands and feet. but included WHSCR.2-pter and a duplication of 2q37. hypotonia.21) was reported by Kohlschmidt et al. growth retardation. and left ptosis (also found in father) with a der(4)(t(4. cleft palate. This 1 year old moderately mentally retarded boy had facial dysmorphism (not further specified). except for the severity of the mental retardation that was severe in the affected patients. and early lethality) initially reported as an autosomal recessive disorder49 was found to be caused by a deletion of 4p16. but this time de novo. cardiac abnormalities (mild pulmonary valve stenosis and large VSD). The majority are de novo but familial cases have been reported. facial dysmorphism (flat philtrum. facial anomalies.41 However. deep set eyes. intrauterine growth retardation. short philtrum). all were microscopically visible except for two sibs who were initially reported by Verloes et al36 as the autosomal recessive GOMBO syndrome (acronym for Growth retardation-Ocular abnormalitiesMicrocephaly-Brachydactyly-Oligophrenia). no language.q13). Haploinsufficiency of the CALL gene at 3p26. and ear abnormalities in common. prominent incisors.37–39 Remarkably. and micrognathia. thin upper lip. Green et al35 narrowed down the critical region for heart defects using five cases and concluded that ATP2B2 is outside this region.3. 4p Terminal deletions of 4p are well known for their characteristic phenotype of Wolf-Hirschhorn syndrome. Other less frequent abnormalities are preauricular pits. posteriorly angulated ears. In the series of 150 severely mentally retarded patients reported by Rio et al.3 deletion. in the series of Cerruti Mainardi et al52 the patients with the most distal deletions only had speech delay and no cat-like cry.47 Subtelomeric deletions of only 100-300 kb from the telomeric end do not result in the WHS phenotype.32.32 in their series of patients screened for subtelomeric deletions.18)(p15. The critical deletion region has been narrowed down to 165 kb at 4p16. This mild variant of WHS is also known as Pitt-Rogers-Danks syndrome with growth retardation.44 5q Two cases with a submicroscopic 5q35.31 It seems that the 2qter deletion polymorphism is the most frequent of all subtelomeric polymorphisms.3 and in approximately 25% of the patients with WHS the (terminal) deletion comprising this region is only detectable by FISH. seizures. horseshoe kidney. The same group reported another unrelated 12 year old female with a similar deletion 5qter and duplication 16qter. microcephaly. the cat-like cry. broad forehead.40 The ATP2B2 gene (PMCA2) centromeric from VHL has been considered a candidate for congenital heart malformations. described a 3 year old girl with severe mental retardation. and low set ears with a deletion that was not detectable by high resolution chromosome analysis. Schinzel.45 The WolfHirschhorn syndrome critical region (WHSCR) is located in 4p16.48 The Lambotte syndrome (microcephaly. downward slanting palpebral fissures. prominent forehead.5 Mb have been described46 that result in a distinct but relatively mild WHS phenotype without malformations. low nasal bridge. Over 25 cases with 3p− syndrome and deletion breakpoints at 3p25-p26 have been reported.51 5p The clinical picture of distal deletions of 5p is known as cri du chat syndrome. downward slanting palpebral fissures. et al several patients even had a phenotypically normal parent with a similar deletion suggestive of a familial polymorphism. triangular face. and a distal tracheal stenosis and a cryptic del 4q34-qter and dup 12p13-pter with a common balanced carrier mother were reported by Fritz et al.14 three cases have been reported.1 that codes for a member of the L1 gene family of neural cell adhesion molecules has been considered to be responsible for a part of the mental impairment.q27) and he had facial dysmorphism (unspecified in the report).jmedgenet.50 4q A few cases with a submicroscopic 4q35-qter deletion have been reported albeit with a limited clinical description. gingival hypertrophy. was reported by Knight et al.388 De Vries.15 Two mentally retarded half sibs both with minor facial anomalies.16) and mild dysmorphic features (dense hair. holoprosencephaly. hypertelorism.42 Higgins et al43 mapped a locus to chromosome 3p25-pter responsible for an autosomal recessive type of non-syndromic mental retardation in a large highly inbred family.53–55 However.1-qter. Large deletions may include the von Hippel-Lindau (VHL) disease gene so screening for VHL in patients with large deletions should be considered.p11. lymphatic . and hypospadias. trigonocephaly. heart defects.3)mat was reported by Riegel et al.t(3. moderately delayed female with an additional trisomy of 16qter owing to a familial t(5.5p) in a 15 year old child with moderate mental retardation. syndactyly. Deletions with a size less than 3.8 Another case was partially trisomic for 6qter owing to a familial t(4.2. mental and growth retardation. Prenatal diagnosis of a fetus with a cryptic t(4. is the result of a subtelomeric deletion located more distal than the deletions that cause the facial features and severe developmental delay in cri du chat syndrome. and low set ears). and renal and gastrointestinal anomalies. ptosis.8 A 5 year old mildly mentally retarded boy with an oval shaped face. and a www.q26.6)(q35. Unlike 4p− and 5p−.29 A similar family (or the same family) with similar clinical features.35 However.3 does not need to have an apparent deleterious effect.12 A limited number of microscopically visible 3qter deletion patients (n=5) have been reported with growth and mental retardation.23 One was a 6 year old. telecanthus. and vesicoureteric reflux. and thick lower lip) and normal growth. where 80% of de novo deletions arise in the paternal germline. and behavioural disturbances. and a lownormal IQ (80-89). Two patients from one family had an additional partial trisomy of 20p owing to a familial t(4.3-qter deletion have been reported so far. The phenotype was caused by a 3pter monosomy and 22qter trisomy as a result of der(3). microcephaly. 3p distinctive facial appearance. Ballif et al34 reported eight cases (5%) in their series of 154 patients with the 2q telomeric polymorphism also found in a healthy parent. normal growth. wide mouth. epilepsy. postaxial polydactyly. short stature. and a micropenis with hypospadias. 3q Only one submicroscopic 3qter deletion (de novo) has been reported so far.22)(p25. Knight et al39 reported a phenotypically normal mother and child both with a terminal 3p25. hypotonia.p13) and they presented with mild mental retardation. large mouth.

Telomeres 389 One microscopically visible de novo terminal deletion of 5q35. scoliosis. One also had a cleft palate and recurrent urinary tract infections. blepharophimosis. digital anomalies. anorectal malformation.p13. flat malar region. and downturned corners of the mouth. and speech delay. However. broad nasal bridge.12)(q27.1-qter region contains two important genes. bifid uvula. inguinal hernia. downward slanting palpebral fissures. agenesis of the corpus callosum. and cardiac defects. and large ears).69 Brackley et al70 reported a 11⁄2 year old.33 Moreover. mild retrognathia. and brain stem dysfunction. and a presacral mass)68 and the Sonic hedgehog (SHH) gene involved with holoprosencephaly (HPE3). severely mentally retarded boy had a de novo 6qter deletion and microcephaly. and hypoplastic genitals. malformed ears). vertebral anomalies (not specified). epicanthic folds. large ears). and brachydactyly. and seizures.3) was included. ear anomalies. some with facial anomalies (notably broad. and low set. Rossi et al12 reported a 1 year old child with congenital chylothorax. facial dysmorphism (not further specified). A familial t(2. PDA. Two severely mentally retarded sibs with a deletion 6qter and a duplication 6pter owing to a paternal pericentric inversion 6 had similar dysmorphic characteristic features: hypoplastic midface. In their series of 70 patients with mental retardation. and seizures. One 4 year old. limb anomalies.8). diastasis recti. thin upper lip.7)(q37. The macrocephaly and thin upper lip might also be the consequence of the partial trisomy 12pter. cleft lip and palate. epilepsy. and marked developmental delay. minor facial anomalies. congenital heart defects (small VSD. 6q In the series of Knight et al.q24).1 Mb of the short arm of chromosome 8. facial dysmorphism (notably ear anomalies. They also reported a 10 year old girl with sacral dysgenesis and moderate retardation. the HLXB9 gene involved with Currarino syndrome (sacral dysgenesis. abdominal hernia. large mouth.57 and a 71⁄2 year old girl with subtle facial anomalies and a complex heart disease including ventricular myocardial non-compaction.16p). The same patient was also reported by Joly et al. hypertelorism. low weight and height. and coarctation of the aorta). small external genitalia. and absence of sacral vertebral fusion caused by a familial der(6)t(6q.64–66 7p Joly et al33 reported a severely retarded 1 month old girl with a deletion 7pter and partial trisomy for 16qter with dolichocephaly. Colleaux et al63 reported a severely mentally retarded boy with a 6qter deletion and a 10qter trisomy with a long and thin face. high nasal bridge.p13). 8p Microscopically visible distal 8p deletions have been associated with growth and mental impairment. long/broad halluces. Wang et al71 reported two sibs with sacral agenesis. microcephaly.1-pter have been reported. bicuspid aortic valve. the current cases predict the presence of a putative gene(s) involved in behaviour in the most telomeric 5. obesity.3-pter owing to a familial t(6.3 has been reported in a mildly delayed 15 month old boy with macrocephaly. . miscarriages. downward slanting palpebral fissures. severely developmentally delayed girl with a submicroscopic der(7)t(2. The frequently observed microcephaly in patients with microscopically visible deletions of 8pter was lacking in both cousins. micrognathia. minor ear lobe anomalies. and severe feeding problems.7)(q37. tented mouth. and long philtrum). Another severely mentally retarded boy with facial dysmorphism (not further specified) was reported in the series of 150 www. and neonatal deaths. palatal malformations (high arched and/or cleft palate).58 Larger and microscopically visible 6qter deletions (6q25qter) have been associated with microcephaly.59–60 7q The 7q36. brachysyndactyly.56 Two cases with a small deletion involving 5q35. which supports the relatively mild phenotypic presentation of submicroscopic 6qter deletions. Eleven cases with microscopically visible deletion 7p22. flat nasal bridge. and cardiac defects in addition to a moderate to severe mental retardation. microcephaly. She had a 7qter deletion owing to a maternal t(7. suggesting that the gene(s) causing the microcephaly were centromeric to the deleted region. upward slanting palpebral fissures. anorectal atresia. and behavioural problems. hypertelorism. anteverted nares with low nasal bridge. Except for the macrocephaly and some minor facial dysmorphisms (thin upper lip and downturned corners of the mouth). deafness. short. telecanthus. retinal abnormalities. genital hypoplasia.q36) and a low birth weight and hypotonia.12)(q36. high forehead.8 a 10 year old mildly retarded boy with macrocephaly and a submicroscopic 6q27-qter and a partial trisomy 12p13. The neck was short and there was fixed left talipes. long eyelashes. small fifth fingers. microstomia. pointed nose. The absence of cardiac defects in the cousins confirmed the more proximal location of gene(s) causing these abnormalities and supports involvement of the GATA4 gene in other reported cases with microscopically visible 8pter deletions. low set. the der(6) was microscopically visible) with minor dysmorphic features (epicanthic folds. broad nasal bridge. Both had a submicroscopic 7q36-qter deletion owing to a familial t(7.3-pter and monosomy 6qter. tall stature. anteverted nares. anteriorly placed anus. no abnormalities were present (C McKeown.q36) was detected. and facial dysmorphism (high. dental anomalies. large tented mouth.1-q53. posteriorly rotated ears. clenched fingers. Moreover. and hypermetropia with a posterior embryotoxon (M Splitt. personal communication). skeletal abnormalities (vertebrae and ribs). hypertelorism. broad nasal tip. bilateral syndactyly of the second and third toes. cardiac defects. epicanthic folds. flat philtrum.jmedgenet. cleft palate. The family history was positive for stillborn children. Two severely retarded uncles with facial dysmorphism and short stature had a similar der(6). micrognathia. long palpebral fissures. personal communication). left microphthalmos and right anophthalmos. smooth philtrum. bell shaped chest. hypertelorism. Sismani et al73 found a 5 year old moderately mentally retarded girl with a subtle 8p deletion (in retrospect also detectable by high resolution banded chromosome analysis) and microcephaly. non-dysmorphic cousins with behavioural problems including inappropriate sexual behaviour and pyromania and a terminal submicroscopic 8p deletion caused by a familial t(8.67 6p One 4 month old moderately mentally retarded boy with a de novo submicroscopic 6p25-pter deletion was included in the study of De Vries et al. Anderlid et al32 also reported three cases with severe mental retardation showing that various levels of retardation are associated with 6qter deletions.11 He had a low/normal growth. There was marked dysmorphism: microcephaly. De Vries et al72 reported two mildly mentally retarded. congenital heart defects. and hypotelorism. nuchal redundancy. hypotonia.61 Batanian et al62 reported a 5 year old mentally retarded boy with a half cryptic translocation 6qter and 2pter (partial trisomy 2p25. The microscopically visible 6p25-pter has been associated with anterior chamber eye defects (corneal opacities/iris coloboma/Rieger anomaly). thin upper lip and high palate.20)(p23. wide supratentorial ventricles and heterotopias.3 have been reported: a markedly delayed 9 month old girl with macrocephaly.

long eyebrows with synophrys. but no trigonocephaly or long philtrum were found in a girl with a cryptic translocation that resulted in a deletion 9p24. short nose/long philtrum. short. tented mouth. there are no reports of microscopically visible 11pter deletions except for one infant with a complex chromosomal rearrangement involving chromosomes 11. In retrospect. However. trigonocephaly. prominent nasal bridge.78 79 This region involved in male to female sex reversal has a high gene density and several candidate genes for sex reversal or gonadal dysgenesis have been identified. and strabismus. and cryptorchidism.3-qter have been reported.81 82 As the clinical presentation of the latter deletion is relatively mild.85 10q 8q No submicroscopic deletions of 8q24. and thrombocytopenia/pancytopenia. long nose. and non-specific facial dysmorphism and a cryptic deletion of 10qter and duplication 20qter was reported by Ghaffari et al. microcephaly. . downturned corners of the mouth. hypertelorism. A severely mentally retarded 32 year old woman with short stature.390 De Vries. Both were severely hypotonic with similar dysmorphism: brachymicrocephaly. thick lips. and Rio et al14 in a severely mentally retarded female with obesity. These are characterised by frontal bossing.13)(q34.12)(p12. severe myopia. In the 10p13/14 region. thin upper lip. However. cleft palate.90 either suggesting that these deletions are probably lethal or simply do not occur. with microcephaly. the derivative chromosome 10 was detectable in the original karyotype. A 10q telomere deletion was reported by Martin et al86 in a 22 month old developmentally delayed boy with pachygyria. upturned nose with broad and prominent root and hypoplastic alae. Rossi et al12 reported a de novo 9qter deletion in a moderately mentally retarded child with facial dysmorphism (not further specified). smooth palmar creases. high nasal bridge. own observation). 2-3 cutaneous syndactyly of the toes. upturned nose with prominent nares. full lips with everted lower lip. high arched palate).14 However.p11.p12) diagnosed by comparative genomic hybridisation. 10p One case with a der(10)t(10. Schinzel. deafness. ano/genital defects. 13. ichthyosis. The youngest also had a congenital heart abnormality (PDA and VSD).84 11q The distal 11q deletion or Jacobsen syndrome is caused by a microscopically visible deletion of the chromosomal bands 11q23. and strabismus has been reported. congenital heart defect. hypotonia. 9p 9q In the series of Knight et al. and/or q25. postnatal growth retardation. et al mentally retarded patients by Rio et al. Upward slanting palpebral fissures and mental retardation. absent eyebrows. upward slanting palpebral fissures. and hyperactivity. ogival palate. severely mentally retarded infant with low birth weight. bilateral preauricular tags. microcephaly. An 8 year old severely mentally retarded girl with a 10qter monosomy and a 16qter trisomy with low birth weight.8 two severely mentally retarded sisters (6 and 11 years old) with a der(9)t(9. and a long philtrum) and mental retardation.12 Colleaux et al63 reported two sibs with severe mental retardation. A 2 year old moderately mentally retarded boy with a der(10)t(10q.16p) has been reported with facial dysmorphism (not otherwise specified) and a hypoplastic penis. West syndrome. the GATA3 gene associated with HDR (hypoparathyroidism. and low set. 11p Only one patient with a submicroscopic 11pter deletion has been reported. micrognathia.15 One had in addition a bifid uvula.92 Terminal deletions extending proximal to 11q23.91 Chromosome band 11q23 is probably associated with craniosynostosis and cardiac defects whereas bands 11q24 and 11q25 are associated with facial dysmorphism and thrombocytopenia. small chin. cardiac defects. However. Patients with microscopically visible 10q26. and cardiac and renal anomalies. cerebellar hypoplasia. and a perineal angioma and der(10)t(10. ptosis. absent corpus callosum. triangular face. micrognathia. a boy with mental retardation. vesicoureteric abnormalities. Winter. foot deformation (not further specified). simplified ears.80 Joly et al33 reported a 2 month old. cryptorchidism.3 are probably lethal.12)(p14. short philtrum.2. strabismus. and sensorineural deafness. coarse facies. so far no mutations have been found in these genes. downward slanting palpebral fissures.q26.33 63 Two moderately mentally retarded sibs with a der(10)t(4. short neck.3). his phenotypically normal mother carried the same telomere deletion.1-pter and normal IQs have also been reported. Both sisters had periventricular white matter changes. and micrognathia. upward slanting palpebral fissures. abnormal genitalia. digit/hand/foot anomalies. low set ears. facial dysmorphism (hypertelorism.10)(q35. The majority of the patients have a microscopically visible deletion with a breakpoint in 9p22.1 do not produce the typical 11q− syndrome. ear anomalies. the trigonocephaly. This 6 year old severely mentally retarded child had epilepsy. short.p13. The mother was a carrier of the balanced t(9.1) were reported. epilepsy. growth retardation (pre.87–89 The clinical features of the 9p− deletion syndrome include dysmorphic facial features (trigonocephaly. cases with a microscopically visible 8p23. and 21.2)pat has been reported. epicanthus. and short upper limbs.13).12 Remarkably. posteriorly rotated ears (O Quarrell. metabolic acidosis. downward slanting palpebral fissures. retrognathia. and developmental delay. it could be possible that the smaller subtelomeric deletions do not cause an abnormal phenotype or have only minor abnormalities. upward slanting palpebral fissures. q24.1-qter deletion (n=20) seem to have a consistent phenotype including mental disability. renal dysplasia) was identified83 and a critical region for the second DiGeorge syndrome locus (DGCR2) was localised proximal to this locus. and also Anderlid et al32 in a 25 year old severely mentally retarded woman with epilepsy. www. seizures. Deletions distal to 11q24.3)mat were reported with a triangular face. mild arthrogryposis and dysmorphic features including sparse scalp hair. and long philtrum can also be seen in patients with a smaller deletion (9p24. enophthalmia. and short fingers. personal communication). Commonly observed features of this syndrome included mild to moderate mental retardation. larger and visible deletions of 10p13-pter have frequently been reported (n>25).and/or postnatal).XY gonadal dysgenesis and the smallest region of overlap has been mapped to the tip of chromosome 9 (9p24. and autism.74–76 BRUNOL3 has been suggested as a candidate gene for the thymus hypoplasia/aplasia in partial monosomy 10p patients.77 Deletions of 9p have been associated with 46. Many patients with a terminal 11q deletion have thrombocytopenia or pancytopenia and this seems to be related to the absence of band 11q24. synophrys. large tongue. However.29 The same chromosomal abnormality was detected in her moderately mentally retarded cousin.jmedgenet. hypertelorism. microcephaly. joint laxity. thin upper lip.

triangular face. 21⁄2 year old boy with a de novo submicroscopic 13q34-qter deletion with low birth weight. 12q Submicroscopic deletions of 12qter have not been reported. he had more dysmorphic features including downturned corners of the mouth.93 The break in chromosome 11 was within the subtelomeric region (a 11q subtelomeric probe hybridised on both translocation chromosomes).3-qter owing to a maternal t(8. high arched palate).and postnatal growth retardation. Routine karyotyping was normal.30 His severely mentally retarded father’s sister had similar clinical features and the same chromosomal abnormalities.95 high palate. wide nasal root.18q translocation that resulted in two cousins with a deletion 11q and with a deletion 18q was described by Schultz et al. However.2. a betaine/GABA neurotransmitter transporter gene expressed in liver.17)(q32. and micrognathia. Clarkson et al31 reported an 18 year old woman with an 11q24. A 5 year old.3. were included in the series of Knight et al. which encodes secreted growth factor-like proteins. two hair whorls. He had normal growth and minimal dysmorphic features (prominent ears and deep set eyes). short neck. these patients showed microcephaly. epicanthic folds. moderately mentally retarded male with pre. hypotelorism. Growth retardation and microcephaly might also be caused by the 6qter abnormality as this has also been described in a boy with partial trisomy 6q26-qter. blepharophimosis. SLC6A12.and postnatal growth retardation including microcephaly. microcephaly. low posterior hairline. flat occiput. facial dysmorphism. and small 5th toes (Homfray. In the series of De Vries et al. short stature.and postnatal growth retardation and microcephaly. two previous children of the mother from different fathers died with MCA (a girl at the age of 5 weeks and a male fetus at 26 weeks’ gestation).3. The mother had a submicroscopic t(14. These cases suggest that the characteristic 14qter phenotype is caused by a deletion of 14q32. 4 year old boy with severe microcephaly. She had features reminiscent of Jacobsen syndrome and a head circumference on the 97th centile consistent with Beckwith-Wiedemann. and prominent tip of the nose. high palate and late tooth eruption. valgus position of the knees. microcephaly. small. we saw a newborn boy with a congenital heart defect and thrombocytopenia. Riegel et al15 reported a moderately retarded.5-11pter owing to a paternal pericentric inversion. severely mentally retarded boy with microcephaly. retinal dystrophy and seizures seem to be restricted to patients with ring chromosomes. and mild facial dysmorphism (hypertelorism). facial dysmorphism (low set simple ears. A cryptic 11q. and WNT5B from the Wnt family. and bilateral hearing loss was presented by Lunt et al (P Lunt. have been suggested as candidates for the mental retardation. 14q One boy with developmental delay. clinodactyly. short fingers. Several microscopically visible 14qter deletions have been reported mostly as a result of a ring chromosome 14. hypertelorism. a pointed chin.p13. and late tooth eruption.q34)pat was reported by Helias-Rodzewicz et al. severe microcephaly. a narrow chest with low widely spaced nipples. anteverted nares. and abnormal palmar creases. Depending on the size of the deletion.3). these patients may be missing one copy of the insulin-like growth factor receptor gene (IGF1R) and some do have features suggestive of Russell-Silver syndrome100–101 www. slender hands. and aggressive behaviour. a long face with flat supraorbital ridges. and digital and dental anomalies. both with a submicroscopic deletion of 12p13. There was a positive family history. high arched palate. widely spaced nipples.jmedgenet. The two mildly mentally retarded sisters (aged 31 and 25 years) had a similar phenotype consisting of obesity. and absence of the distal interphalangeal creases of the third and fourth fingers. Like the submicroscopic case. small mouth with a 15q No submicroscopic deletions of 15q26. high arched palate. Her brother was moderately mentally retarded and had like his sister pre. personal communication). epicanthic folds. a 15 year old. q26. personal communication). single palmar crease. An adult woman with the derivative chromosome 11 had mild mental retardation. flat philtrum.11 two cases with a submicroscopic 13qter deletion were included. and a wide columella).13)(p16. and delayed bone age (C McKeown. moderately disabled boy and his mother with (unspecified) learning difficulties were reported by Baker et al23 95 with a 12pter deletion. ptosis. Similar 14q− features were observed in a boy with an apparently balanced translocation between 14q and 21p.8 The girl was mildly mentally retarded with pre.3. micrognathia. micrognathia.3. However. a small mouth. oval shaped face. open mouth with downturned corners). Cases with a ring chromosome 15 have de novo deletions of the distal part of 15q (q26. abnormal ears. camptodactyly. brachymesophalangy V. and had various dysmorphic features including small overfolded ears. thin upper lip.p13.99 A minority have cardiac and/or urogenital abnormalities. mild facial asymmetry. and a 46.3 with FISH. mild thoracic kyphoscoliosis.q34).3-qter and that blepharophimosis in combination with features such as microcephaly are strong indicators to perform 14qter FISH analysis. skeletal muscle. and muscle weakness resulting in lordosis. heart. hypertelorism. Because of the clinical features. 13q Kleefstra et al96 reported two sisters with a submicroscopic 13q34-qter deletion and partial trisomy for 8q24. reflux/ vomiting. long. thick ears. and pes planus. 12p A 12 year old girl and her 8 year old brother.Telomeres 391 Recently. personal communication). short nose with bulbous tip.13)(q24. She had a normal birth weight.3). right sided aortic arch. microphthalmia.3-qter have been reported. skin atrophy of the lower limbs. bulbous nose with large nares.XY. Baker et al23 reported a 17 year old.97 Van Karnebeek et al98 reported another example of a submicroscopic 14q32. blepharophimosis. The other was a moderately mentally retarded. and talipes valgus with absence of the fifth toe nails. short feet with large toes. who was shown to have a submicroscopic terminal deletion of 14q32. was macrocephalic at 18 years (OFC >98th centile) with short stature (<3rd centile). and brachydactyly. flat philtrum.3-pter and a partial trisomy 6q27 owing to a maternal t(6. and/or q26. fifth finger camptodactyly. blepharophimosis. low set ears. narrow elongated face. mild facial dysmorphism (thin lips. long beaked nose. persistence of some primary . flat nasal bridge. and placenta with widespread distribution in the brain. broad prominent nose. One 17 year old severely mentally retarded girl had a submicroscopic 13q34qter deletion and a partial trisomy 1q44-qter. and no dysmorphic features. Two genes in the region.94 Moreover. short fingers with clinodactyly.1) and are characterised by growth and mental retardation.31-qter in mildly mentally retarded girl.12)(q27. facial dysmorphism (high forehead.3-11qter deletion and a duplication of 11p15.der(13)t(4. FISH with a subtelomeric 11q probe was performed and showed a de novo deletion.

small preauricular tags.12 Werner at al110 reported a 5 year old boy with a small distal interstitial deletion of chromosome 16 (del(16)(q23.3-pter and a partial trisomy of 1p36. moderate developmental delay.18)(q28.33-pter. very broad almost bifid nose. small carp-like mouth.2)) and bilateral coloboma of the iris. and a single maxillary incisor.p13. and abnormal toe position). midfacial hypoplasia. small mouth with thin lips and small chin) caused by a der(16)t(16. She had severe myopia with bilateral choroidoretinal atrophy. and epicanthic folds. bushy eyebrows.117 this gene might also be involved in causing the extreme thinness in the former single case No further submicroscopic deletions of 17q25-qter have been reported so far. none of them is a submicroscopic deletion of 18p11.3-pter and duplication of 8q24.3-qter with tuberous sclerosis. pectus excavatum.3 and did not find any discernible phenotype other than α-thalassaemia. short palpebral fissures.1q24.86 17q One de novo 17qter deletion has been reported in a 15 year old child with moderate mental retardation. open mouth appearance. has been suggested as a good candidate gene for the mental retardation.2-pter and a partial trisomy for 2p25-pter was reported who had normal intelligence. coxa valgus. flat nasal bridge. including bitemporal narrowing with sloping forehead. congenital nystagmus. slim fingers. weight. and OFC <3rd centile) with an unusual face.3 (>1 Mb).16)(q29. inguinal hernias. and kidney anomalies. marked hypertelorism with epicanthic folds. and bilateral talipes equinovarus with a deletion telomeric to LIS1. seizures. cleft palate. widely spaced nipples. Remarkably. downward slanting palpebral fissures. Warburton et al105 reported two sisters with a submicroscopic subtelomeric deletion of 16p13. deletion of the LIS1 gene.p13. cardiopathy (not further specified). and undescended testes in males. adult polycystic kidney disease. However. ataxia. slightly upward slanting palpebral fissures. et al 16p The combination haemoglobin H disease and mental retardation was first reported by Weatherall et al in 1981. Her younger sister showed a more or less similar phenotype. flat nasal bridge. 16q Only one submicroscopic deletion of 16qter has been reported which was caused by a 16q. Most patients have deletions in 18q21. As the growth factor receptor bound protein 2 located on 17q25. The 18q− or de Grouchy syndrome is characterised by mental retardation. autistic features. 700 kb from the telomeric end. The oldest presented with a left corneal dermoid cyst and a unilateral iris coloboma at birth with preauricular skin tags and a patent ductus arteriosus. Several families with a cryptic translocation and Miller-Dieker syndrome have been described. and a few facial anomalies (broad forehead. They showed mild facial dysmorphism similar to previously described cases and a low birth weight. and a large nose and mouth). precocious puberty.3). Holinski-Feder et al104 reported 10 affected family members with ATR-16 syndrome caused by a subtelomeric submicroscopic der(16)t(3. small. and behavioural problems. However.3). pes equinovarus. cryptorchidism. The extremities showed long. crowded midface. hypotonia. and facial dysmorphism (telecanthus. facial anomalies.19)(p13. hypotonia.1 has been suggested as a candidate locus for Silver-Russell in two translocation patients. all suggestive of Goldenhar syndrome. A locus for cataract has been suggested within 1 Mb of 16qter based on findings in patients with ring 16. Isolated lissencephaly has been described in patients with a balanced translocation with a breakpoint in the LIS1 gene. cerebral atrophy.q23) who was severely mentally retarded with growth retardation (including microcephaly). and various limb anomalies (for example. and facial anomalies (not further specified) and a partial agenesis of the corpus callosum. cortical atrophy. Winter.118 and Gripp et al119 reported four missense mutations in the TGIF gene in 268 patients with HPE. glandular hypospadias. wide mouth with downturned corners.108 Notably. This suggests that the additional phenotypic effects are caused by larger deletions of 16p13. which is characterised by severe mental retardation. broad. 18p Although numerous cases with microscopically visible 18pter deletions have been reported. Eussen et al106 reported a boy with a submicroscopic deletion of 16p13. more distal deletions (18q23) may also result in the classical phenotype. and extreme thinness12 and another 17qter deletion and 12qter duplication. postnatal growth deficiency. in a mildly mentally retarded girl with pre. and ulnar deviation of the middle fingers.3. and dental malocclusion.115 Mutchinick et al116 described an 8 year old girl with mental retardation. hearing loss (most often resulting from narrow or atretic auditory canals). Notably. Besides the α-thalassaemia/mental retardation.3-qter.19p rearrangement. agenesis of the corpus callosum. microcephaly. The SOX8 gene. but there exists a wide phenotypic variability.111 18q 17p Terminal deletions of 17p result in a distinctive phenotype.3. and cerebral atrophy. owing to a paternal translocation. midfacial hypoplasia. personal communication). maxillary hypoplasia. Brown et al107 reported a newborn with cranial tubers and subcortical renal cysts suggestive of tuberous sclerosis and additional atypical features such as bilateral nasal colobomas of the eyes. ventricular septal defect. and a narrow mouth with downturned corners consistent with 18q deletion syndrome. broad nasal tip. facial dysmorphism (not further specified). suggesting that such small 18pter deletions are only associated with mental retardation if (some degree of) holoprosencephaly is present. microcephaly. The deletion 18pter patients have short stature with variable facial dysmorphism such as a round face. proximally placed thumbs.102 Wilkie et al103 showed in 1990 that this α-thalassaemia/mental retardation syndrome was caused by a terminal (submicroscopic) deletion of 16p13. Miller-Dieker syndrome. partial agenesis of the corpus callosum. and a small hypoplastic scrotum (R Winter. At 15 years of age she was small ( .124 Slavotinek et al125 reported a severely mentally retarded 15 year old girl with a de novo submicroscopic 18q23-qter deletion and growth retardation. 10% of cases have holoprosencephaly for which the putative HPE4 gene has been mapped to 18p11. hypertelorism. phenotypically normal subjects with telomeric 17p deletions up to 600 kb have been reported.3.392 De Vries. short stature. lissencephaly. long fingers. tapering fingers and fifth finger clinodactyly. seizures. hypernatraemia.and postnatal growth retardation. a 37 year old female with a (visible) deletion 18p11.120 Familial microscopically visible 18p deletions have been reported121–123 and some patients with normal or borderline intelligence have been observed. and hypomelanosis of Ito.jmedgenet.112–114 The lissencephaly in Miller-Dieker syndrome is the result of www.3. It has been known for some years that microdeletions can also cause this syndrome and the critical region is within the terminal band 17p13. This 11 year old child had moderate mental retardation. short stature. 5th finger clinodactyly. Knight et al8 reported in their series a boy with a de novo der(18)t(X. hypotonia. Horsley et al109 studied 21 independent deletions from the 356 kb telomeric region of 16p13. the associated dysmorphic features are mild: hypertelorism. Schinzel. growth deficiency.

narrow auditory canals.22) and the 22qter phenotype. and DiamondBlackfan anaemia.136 Anderlid et al32 reported a mildly mentally retarded 34 year old woman with probably a very small de novo 22qter deletion and autistic disturbance. This selection has been based on the “chromosomal phenotype” as has also been shown by several groups. and abnormal white matter. and dysplastic ears. and Kallmann syndrome (KAL). more than 10 cases with a submicroscopic or cryptic deletion have been reported. hypertelorism. nystagmus.132 133 22q Most reported cases with a 22q13. severe expressive language delay leading to absence of speech. Another limitation is that most of the informative markers are located a relative large distance from the telomere and therefore small subtelomeric deletions can easily be missed using this method.Telomeres 393 Vogels et al126 described a family with a cryptic translocation t(5. Another severely mentally retarded girl with a de novo 22qter deletion and 20qter duplication was reported with facial dysmorphism.137 Xp Numerous patients with deletions of Xpter have been reported and the clinical presentation is dependent on the deleted genes and can for males result in a combination of the following disorders: short stature (SS). PAC. Microscopically visible Xqter deletions are associated with ovarian failure in females.3 deletion cases. punchedout lesions of the retina. The second method is FISH of probes (BAC. 19q No submicroscopic deletions of 19q13. downturned corners of the mouth. ptosis. or P1 clones) localised in the subtelomeric region to metaphase chromosomes. Small visible deletions of 21q22.93 Two adult men in this family had a subtelomeric deletion 18q and duplication 11q.3-qter have been reported. epicanthic folds.3 and ring chromosome 21 have been associated with holoprosencephaly. although the majority of the microscopically visible cases do have dolichocephaly. The facial features do not seem to form a characteristic pattern. First is the use of polymorphic microsatellite markers localised in the subtelomeric region. He had epilepsy from 7 years of age and delayed secondary dentition. and red cell abnormalities.63 148 A disadvantage of this technique is that for detecting hemizygosity for a certain marker. Currently.18)(qter. www. micrognathia. Precht et al134 reported two cases with some similarities with Angelman syndrome. the deletion of 19pter in the latter case is questionable because of the poor quality of the chromosome analysis. behavioural problems) and features that are observed in 5q duplication (umbilical and inguinal hernias and congenital heart defect). Clinically there is a much similarity with the case reported by De Vries et al145 with a submicroscopic Xp22. ichthyosis (XLI). 21q No submicroscopic deletions of 21q22. 19p No submicroscopic deletions of 19p13-pter have been reported. non-specific deafness.138 139 One gene for short stature. In 1984 only one patient with a visible partial deletion of 19p was reported with a prenatal onset of growth retardation (including microcephaly).3 -qter deletions in 44 cases with features suggestive of Angelman syndrome but without the characteristic 15q abnormalities.32 ProSAP2 (the human homologue of the proline rich synapse associated protein 2) has been suggested to be causative for the 22qter deletion syndrome after identification of a disruption of this gene in a patient with a balanced t(12. a thin corpus callosum. His mentally retarded mother had the similar 20pter deletion with similar facial characteristics. umbilical hernia. Another familial cryptic translocation (11q. However. which is a considerable proportion of cases with mental retardation of unknown cause.127 However. might actually be a little overestimated.143 Tobias et al144 reported a boy with a normal intelligence and a telomeric deletion including the STS locus as the result of a der(X)t(X. mental retardation (MRX). pervasive behaviour.21). One interesting case with general overgrowth and features suggestive of FG syndrome has been reported. and a small mouth with a short philtrum). skeletal malformations. either FISH with telomere specific probes or molecular analysis based on polymorphic markers. flat nose.140 was also shown to be mutated or deleted in families with Leri-Weill dyschondrosteosis. De Vries et al135 found no evidence for 22q13. facial dysmorphism (long face.Y)(p22.3 has been associated with other clinical features: hypotonia. This is likely to change when new techniques will allow for larger number of patients to be tested.3-qter have been reported. Unfortunately. Microdeletions in 19q13. deep set eyes with upward slanting palpebral fissures.2 have been associated with mental retardation. the short stature homeobox containing gene (SHOX). with this technique isodisomy can be detected. In addition to the developmental delay.23 Xq No submicroscopic deletions of Xq28-qter have been reported. and discrete facial findings. other family members were not available for testing. They were marginally mentally retarded without dysmorphic features. genital hypoplasia. are labour intensive.18q) was described by Schultz et al. ataxic gait.11 14 15 30 Such selection has been required for some time being the currently available techniques. as in the major studies published so far selection of cases has probably occurred.q11.3 deletion have been microscopically visible but since the development of submicroscopic screening methods of the telomeres. DNA samples of the parents are required. epilepsy.131 20p Baker et al23 reported a 10 year old moderately mentally retarded male with a submicroscopic deletion of 20pter and microcephaly. and flat feet. the facial features are even more subtle and variable. simian creases.qter) that had resulted in unbalanced offspring with features characteristic of the 18q deletion syndrome (growth deficiency. For the few submicroscopic 22q13. and subtle facial dysmorphism. 20q No submicroscopic deletions of 20q13.jmedgenet.128–130 This suggests a contiguous gene syndrome which includes the ribosomal protein S19 that is mutated in Diamond-Blackfan anaemia.4-qter have been reported. However.146 DISCUSSION The identification of subtelomeric rearrangements as a cause of mental retardation has made a considerable contribution to diagnosing patients with mental retardation and counselling of the families involved. monosomy 22q13. The latter boy however was mentally . The initial problem of cross hybridisation. high palate.141 142 Although a putative locus for mental retardation (MRX49) has been located distal to the STS locus. low set ears.31-pter deletion with a breakpoint just upstream of the STS locus.31. X linked recessive chondrodysplasia punctata (CDPX). two techniques are commonly used for detecting subtelomeric abnormalities (reviewed by Knight and Flint147). The reported frequency of subtelomeric deletions of ∼5%.

retardation. a de novo telomeric deletion requires a single chromosomal breakpoint in contrast to the double break with interstitial deletions and might therefore occur more frequently. 12q.17 136 158 although sometimes the number of patients is too limited (yet) to identify a phenotype. 18q.2 deletion. ACKNOWLEDGEMENTS We wish to thank Drs Kets. the majority of the known interstitial microdeletions do have mental retardation as the major clinical presentation. the 2q subtelomeric region. the array CGH will eventually allow for a “whole genome screen”. at the moment. a collaborative European consortium has started to facilitate the collection and subsequently the distribution of this knowledge with EU funding (ECARUCA. the deletion of the entire short arm of chromosome 18. this knowledge will not be easy to obtain. 3p*. 20q. and 21q (table 2). 15q. However. www. 17q 8q. B B A de Vries was supported by a grant from ZON-MW (The Netherlands). The www. Therefore. This will be essential for counselling the parents and family involved. 16q. even microscopically visible deletions exist which do not cause mental retardation in all probands. the phenotype is quite consistent. 8p. et al which hampered this method for certain subtelomeres. 12q. Newbury-Ecob. Because of the relatively novelty of the technique. The future will tell us which of the above explanations/mechanisms are involved in these rare subtelomeric rearrangements. but. When new techniques become available. new techniques have been developed to overcome the limitations of these commonly used techniques. This technique has also been proven to work for screening of subtelomeric chromosome abnormalities. When should a submicroscopic deletion be considered to be the reason for the mental retardation? If the microdeletion has been observed in other patients with mental retardation either within the same family or in unrelated cases. 20p* 3q. 18p and 19p. the chromosomal phenotype. Although multiplex FISH (M-FISH) allows for the detection of cryptic abnormalities as well. the deletion could mostly be regarded as causative. 22q 1q. Armour et al150 developed the multiplex amplifiable probe hybridisation (MAPH) methodology which allows assessment of copy number at specific genetic loci. The yield in diagnosing new chromosomal abnormalities related to mental retardation is likely to be considerable. 12p. 17p 1p. It is remarkable that for certain subtelomere regions no deletions have been reported so far. 19p.394 De Vries. 19q. As most newly identified interstitial deletions will be single cases. This technique is shown to be a rapid and sensitive automated procedure. but it requires an array facility. clinical resemblance between patients has been sought and found.8 the Cytocell Ltd Multiprobe technique. even more new microdeletions will be detected which will be at first single cases only. is in a considerable proportion of cases not even associated with mental retardation.157 Moreover. has largely been overcome. the telomeric deletion appeared to be de novo.151 Veltman et al152 reported an array based comparative genomic hybridisation (CGH) to detect subtelomeric chromosome rearrangements. but that does not explain why certain large microscopically visible deletions involving the subtelomeric region are reported whereas submicroscopic ones have not been found. most commonly involving mental retardation. PAC. . this latter technique is still labour intensive. for most of the subtelomeric deletions the number of patients with similar deletions reported is still limited or no cases have been reported at all. Another problem is the (telomeric) polymorphisms. and P1 clones are within 500 kb from each telomere and are therefore suitable to detect small subtelomeric rearrangements. 7p. and Bongers for kindly providing clinical photographs. for example. However. Such a collection will not only help patients and their families and clinicians but will also give more insight into molecular mechanisms involved in the aetiology of mental retardation and malformation syndromes. Schinzel. For some of the common forms of subtelomeric deletions such as 4p.ecaruca. This second generation set of telomere specific BAC. Like for the subtelomeres.149 Currently. However. the subtelomeric microdeletions are more likely to give a phenotypic effect. 7q. 5p. some subtelomeric deletions may just not occur because of stability of the specific subtelomeric chromosome region. Lynch. Secondly. 13q. Another explanation is that these deletions are not associated with a “characteristic” chromosomal phenotype.jmedgenet. Finally. 6p. If facilities to identify interstitial microdeletions are in place then it is likely that large numbers of new deletions will be found. Extension to thousands of markers equally divided over the genome will make such a scan very sensitive for detection of cryptic chromosomal abnormalities. 2q. all the subtelomeres can be tested on a single chromosome metaphase slide with a device developed by Knight et al. 9p. The majority of patients with subtelomeric deletions have just been diagnosed by using the telomere screening method with limited clinical guidance.8 It is likely that the whole genome is vulnerable to similar. 19q. for instance lacking the mental Table 2 Frequency of specific submicroscopic subtelomere deletions No of reported cases >50 11–50 2–10 Single None Telomere region 4p. Winter. then comparison between other patients with similar deletions will be required. 5p. 6q. However. Flinter. and 9p (table 2). we will have to collect similar cases in order to identify the clinical presentation which will allow proper genetic counselling of the family. albeit interstitial. Therefore. but will certainly be found in the future. such as 8q. First.73 Another promising technique is multiplex ligation dependent probe amplification (MLPA) which unlike MAPH does not require immobilisation of sample nucleic acids with additional washings. for example. Maybe certain deletions are lethal.154–156 it is (or is likely to be) less sensitive than a microsatellite scan or a microarray CGH. 18p. one of the well known interstitial microdeletions. 11q. If the set of clones is extended over other regions of the genome. So far these interstitial microdeletions have been found because of their characteristic phenotype. All these new techniques will also allow for detection of other as yet unknown submicroscopic interstitial deletions in the genome. Of course there are some major differences. An adequate collection of clinical data of those rare cases will be required in order to help the clinician and the family to understand the meaning of these findings in their patients and their relatives. 11p. 5q. 9q. which might be more common than previously considered. 10p. microdeletions. it is conceivable that such deletions have just not yet been found simply because they are rare. 18p. 14q. costly as well. 4q. because of the gene richness of these regions. for example. the 22q11. In almost half of the patients. 21q *More than one case but within one family. 19p. After identification of similar telomeric deletions. 2p*.34 When other clinical features are part of the clinical presentation in a single patient. The increasing number of very small chromosomal aberrations that will be found in the near future will confront the clinician with various problems. Rosenberg et al153 showed that a genome wide microsatellite scan can be used to detect submicroscopic chromosomal aberrations. Using a 400 microsatellite marker panel. 16p. and therefore are simply not looked for in the right patient population.

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